Endothelial cell derived relaxing factor has been identified to be nitric oxide and the pathway responsible for its synthesis in human cells has been partially elucidated. Further, antagonists of this pathway have been synthesized and shown to block the hypotension caused by tumor necrosis factor, an important mediator of septic shock. In these investigations, the nitric oxide pathway will be examined in patients with septic shock and in normal volunteers given endotoxin. We will look for evidence of nitric oxide synthase induction during the systemic inflammatory response to clarify the role of this pathway in human disease. The initial phase of this project has begun in normal volunteers given either sodium nitroprusside or endotoxin. Methods have been developed to measure exhaled nitric oxide, serum and urine nitrite/nitrate concentrations and cGMP in addition to standard cardiovascular and pulmonary physiology. Future studies will examine induction of nitric oxide production in the lung after intrabronchial administration of endotoxin. These latter experiments are being conducted in conjunction with in vitro studies examining the role of nitric oxide in modulating the interaction between human neutrophils and bronchial epithelial cells (Z01-CL-0114-03-CCMD).